A number of phenotypic traits may predispose humans to the development of obstructive sleep apnea (OSA). These traits may be altered over time in response to a variety of perturbations that accompany OSA, ultimately resulting in the exacerbation of this disorder. Our proposal will examine whether one phenotypic trait, the ventilatory sensitivity to carbon dioxide and oxygen, is increased in response to intermittent hypoxia (a hallmark of OSA), and whether this increase leads to exacerbation of OSA. Moreover, because oxidative stress following intermittent hypoxia has a role in enhancing respiratory drive in animals, we will examine whether this mechanism contributes to increases in ventilatory sensitivity and ultimately exacerbation of OSA. We will also determine whether treatment with antioxidants reverses this effect. To achieve our goals the following specific aims will be addressed: Specific Aim 1 is designed to measure the ventilatory response to carbon dioxide in the presence of sustained hypoxia and hyperoxia during wakefulness, using a modified rebreathing technique, before and after exposure to acute intermittent hypoxia (AIH) for 7 consecutive days (chronic intermittent hypoxia - CIH). Specific Aim 2 is designed to measure nocturnal respiratory drive and apnea severity before and after AIH, and to determine whether the impact of AIH on these measures is intensified after CIH. Measures of nocturnal respiratory drive will be obtained by examining changes in the ventilatory response to hypoxia and the rate of change of esophageal pressure during apnea. Specific Aims 3 &4 will measure oxidative stress before and after AIH, and will determine whether antioxidant treatment mitigates increases in ventilatory sensitivity to carbon dioxide, nocturnal respiratory drive and ultimately apnea severity following exposure to AIH. The proposed aims are likely to yield critical insight into the impact that intermittent hypoxia has on ventilatory sensitivity and apnea severity. Moreover, our findings may provide the rationale for using antioxidants as a potential treatment for OSA. This treatment could be particularly useful in individuals who suffer from mild or moderate forms of OSA when used in conjunction with other potential innovative therapies.